Noonan syndrome (NS) is an autosomal dominant disorder characterized by dysmorphic facial features, proportionate short stature, and heart disease, i.e., pulmonic stenosis and hypertrophic cardiomyopathy most commonly (Noonan, Am. J. Dis. Child. 1968, 116:373-380; Allanson, J. Med. Genet. 1987, 24:9-13). Webbed neck, chest deformity, cryptorchidism, mental retardation, and bleeding diatheses constitute other frequently associated findings. NS is a relatively common syndrome with an estimated incidence of 1:1000 to 1:2500 live births.
At present there is no blood test for diagnosing Noonan syndrome, or any other conclusive genetic test for this disease. The diagnosis depends on recognition of the symptoms by a knowledgeable doctor. However, substantial phenotypic variations, including mild or subtle cases, make the diagnosis difficult. Furthermore, the facial characteristics become less apparent with progressing age, and so the condition sometimes remains undiagnosed. In addition, whereas the disorder may be suspected in utero when fetal ultrasound show excess fetal fluid, such as nuchal edema, there is no reliable test for Noonan syndrome during pregnancy.
A number of therapeutic or surgical treatments are available to alleviate various symptoms of Noonan syndrome. Such symptoms include heart defects, undescended testicles, or excessively short stature. However, no therapeutic treatment of the underlying disorder has been proposed so far, absent identification of the causative gene of the Noonan syndrome.
Physical mapping of the genetic region involved in Noonan syndrome has been described. A 5-cM region (NS1) on chromosome 12q24.1 has been disclosed, and genetic heterogeneity has also been documented (Jamieson et al., Nat Genet 1994;8:357-360; Brady et al., Eur J Hum Genet 1997;5:336-337; Legius et al, Eur J Hum Genet 1998;6:32-37; van Der Burgt, and Brunner, Am J Med Genet 2000;94:46-51). However no specific gene has been identified.
Therefore, there remains a need to identify a specific gene involved in Noonan syndrome. Such identification would immediately provide strategies for diagnosis, in particular early diagnosis, and treatment of this disorder.